Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes

Article abstract of DOI:10.1021/jacs.8b00643

Metal-catalyzed silylative dehydration of primary amides is an economical approach to the synthesis of nitriles. We report a copper-hydride(CuH)-catalyzed process that avoids a typically challenging 1,2-siloxane elimination step, thereby dramatically increasing the rate of the overall transformation relative to alternative metal-catalyzed systems. This new reaction proceeds at ambient temperature, tolerates a variety of metal-, acid-, or base-sensitive functional groups, and can be performed using a simple ligand, inexpensive siloxanes, and low catalyst loading.

Full text of DOI:10.1021/jacs.8b00643

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Communication
Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-
Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes
Richard Y. Liu, Minwoo Bae, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00643 • Publication Date (Web): 22 Jan 2018
Downloaded from http://pubs.acs.org on January 22, 2018
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Mechanistic Insight Facilitates Discovery of a Mild and Efficient
Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using
Hydrosilanes
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Richard Y. Liu,‡ Minwoo Bae,‡ Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Supporting Information Placeholder
group appear very prone to rapid elimination. For instance, a copꢀ
per alkoxide is thought to be released through synꢀelimination in
the mechanisms of CuHꢀcatalyzed hydroacylation using unsatuꢀ
rated acids,7h redox relay hydroamination,7p and reductive couꢀ
pling with anhydrides.7q Suspecting by analogy that a particularly
facile synꢀelimination might also be involved here, we proposed
the catalytic mechanism in Figure 1C.
ABSTRACT: Metalꢀcatalyzed silylative dehydration of primary
amides is an economical approach to the synthesis of nitriles. We
report a copper–hydride(CuH)ꢀcatalyzed process that avoids a
typically challenging 1,2ꢀsiloxane elimination step, thereby draꢀ
matically increasing the rate of the overall transformation relative
to alternative metalꢀcatalyzed systems. This new reaction proꢀ
ceeds at ambient temperature, tolerates a variety of metalꢀ, acidꢀ,
or baseꢀsensitive functional groups, and can be performed using a
simple ligand, inexpensive siloxanes, and low catalyst loading.
Due to their unique reactivity and activating ability, nitriles are
important functional groups in organic synthesis.1 Moreover, cyaꢀ
nated compounds frequently find applications in medicinal, bioꢀ
logical, physical organic, and materials chemistry.2 Alongside
substitution and rearrangement reactions that form C–CN
bonds,3,4 the generation of nitriles by dehydration has been an
important functional group interconversion,5,6 which is traditionalꢀ
ly accomplished using harsh, acidic dehydrating reagents such as
P4O10,5a POCl3,5b SOCl2,5c or TiCl4.5d
Recently, several research groups have reported silaneꢀbased
dehydration reactions of primary amides, typically catalyzed by
metals such as iron, ruthenium, or fꢀblock elements.6 These eleꢀ
gant approaches feature several advantages: inexpensive hyꢀ
drosilanes can be employed, only hydrogen gas and nonꢀtoxic
siloxanes are produced as byproducts, and highly acidic and basic
conditions can generally be avoided. Nevertheless, the reported
examples require prolonged heating at refluxing temperatures and
exhibit limited substrate scope, particularly if aliphatic amides are
employed. It is thought that the harsh conditions are necessitated
by the difficulty of a siloxaneꢀreleasing thermal synꢀelimination
step that is involved in each of the reaction mechanisms.6c,d,g,h,p
Indeed, density functional theory (DFT) calculations suggest that
this barrier is high for a typical silyl group (see Figure 1B).
Copper–hydride(CuH)ꢀcatalyzed transformations have been exꢀ
tensively explored by our laboratory and others. These studies
have focused mostly on stereoselective hydroamination, reduction
and, more recently, hydrofunctionalization reactions.7 During our
studies on imine allylation under CuHꢀcatalysis,7j we were surꢀ
prised to find that rather than undergoing the desired coupling
reaction, substrates containing a primary amide functional group
appeared to rapidly dehydrate to the corresponding nitriles at
room temperature. Although initially we did not expect silylative
dehydration under such mild conditions, we have previously reꢀ
ported that copper(I)ꢀalkyl intermediates bearing a βꢀleaving
Figure 1. Overview of AmideꢀtoꢀNitrile Conversion. The comꢀ
puted transition state structure for the boxed step is shown in the
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a
bottom left. Density functional theory (DFT) free energy calcuꢀ
lations performed with 1,2ꢀbis(dicyclohexylphosphino)ethane as
With this hypothesis in mind, a more systematic study of this
reaction initially focused on the examination of a selection of
common monoꢀ and diphosphines as supporting ligands. Using
each of these, we subjected primary amide 1a to typical condiꢀ
tions for CuH catalysis (Table 1). At ambient temperature, most
ligands, in combination with Cu(OAc)2, were effective in promotꢀ
ing the formation of the desired nitrile product 2a. In general, the
use of chelating diphosphine ligands proved to be superior to
monophosphine ligands. We chose DCyPE due to its effectiveness
and commercial availability.9 We note that PMHS
(polymethylhydrosiloxane), a very inexpensive polysiloxane, can
be used as the stoichiometric dehydration agent (Table 1, entry 8);
however, for most examples we have employed monomeric
DMMS (dimethylmethoxysilane) since it can be obtained in more
consistent quality and more uniform composition from commerꢀ
cial sources.10,11,12
1
2
3
4
5
6
7
8
the
supporting
ligand
using
M06/SDDꢀ6ꢀ
311+G(2d,p)/SMD(THF)//B3LYP/6ꢀ31G(d).
We expected that the dehydrogenative silylation of a primary
amide should first yield a monosilyl imidate. The Oꢀ and Nꢀbound
isomers are predicted by DFT to rapidly equilibrate, consistent
with previous studies.6c,d,g From here, most reported methods are
thought to proceed through a second silylation to produce a disilyl
imidate, a species that we identified as the probable kinetic sink.
When we performed DFT calculations in order to model the
mechanism of our process, we found a much lower energy alterꢀ
native pathway in the case of a bisphosphineꢀligated copper cataꢀ
lyst. σꢀBond metathesis to form the disilyl imidate from the preꢀ
ceding intermediate is predicted to be slow, with a free energy
barrier of over 30 kcal/mol; however, a nearly barrierless copperꢀ
alkoxide elimination is expected to proceed rapidly, which directꢀ
ly forms the desired nitrile product and LnCuOSiR3. The latter can
close the mechanistic cycle through σꢀbond metathesis with addiꢀ
tional hydrosilane.8
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Table 2. Yield Comparison with Alternative Methods of
Nitrile Dehydrationa
CONH2
Me
CONH2
CONH2
S
Ph
CONH2
Method
Ph
Although concerted elimination to generate an spꢀhybridized
carbon center is relatively rare, we note that an analogous process,
which generates a ketene, is proposed to be involved in CuHꢀ
catalyzed unsaturated acid reduction with support from both DFT
calculations and multiple mechanistic experiments.7f The facile
nature of this elimination step relative to the uncatalyzed eliminaꢀ
tion from the disilyl imidate may be due primarily to greatly reꢀ
duced strain in the fourꢀmembered transition state. In the copperꢀ
catalyzed elimination transition state, the Cu–O and Cu–N bonds
(251 pm and 199 pm) are longer on average than the Si–O and Si–
N bonds (187 pm and 200 pm) in the corresponding disilyl imꢀ
idate elimination transition state, likely due to the larger size of
Cu compared to Si. This reduced strain, combined with the therꢀ
modynamic favorability of forming a C–N triple bond, results in
particularly rapid elimination.
Cl
MeO
OH
2% [Cu], DMMS, rt
5% [Fe], DEMS, 100 °C6g
5% [Fe], DEMS, rt
POCl3, Et3N, rt
97%
85%
<5%
98%
86%
85%
23%
<5%
27%
48%
80%
93%
49%
<5%
42%
68%
75%
24%
38%
13%
T3P, 100 °C
5% TBAF, PhSiH3,
100 °C6p
87%
7%
8%
62%
16%
47%
5%
5% TBAF, PhSiH3, rt
<5%
a
Yields were assessed by GC analysis of the crude reaction
mixture, using dodecane as an internal standard. See supporting
information for reaction conditions and details.
When we compared this optimized procedure with representaꢀ
tive classical and modern methods (Table 2) on four simple subꢀ
strates, we found that only our system provided high yields on
each of these amides. We determined that a wide range of amides
could be converted efficiently to the corresponding nitrile under
these optimized conditions (Table 3). Simple αꢀprimary (2b, 2c),
secondary (2a), and tertiary (2d) amides were all compatible subꢀ
strates. In addition, a variety of aromatic amides were suitable
substrates, regardless of whether they bore electronꢀwithdrawing
(2g), ꢀdonating (2h), or protic (2f) substituents. Moreover, several
classes of heterocyclic amides, including a thiophene (2i), pyriꢀ
dine (2l), pyrrolidine (2j, 2k), and piperidine (2m) were successꢀ
fully transformed. The mild reaction conditions were compatible
with (hetero)aryl halides (2g, 2i), and acidꢀsensitive carbamate
protecting groups like Boc (2l). Importantly, since there is no base
or acid generated in the reaction, no epimerization of labile αꢀ
stereocenters is observed during the process (2k, 100% enantiꢀ
ospecificity).
Table 1. Evaluation of Conditions for Amide Dehydrationa
Entry
Ligand (n)
nonec
Silane (equiv)
DMMS (3)
DMMS (3)
DMMS (3)
DMMS (3)
DMMS (3)
DMMS (3)
DMMS (2.5)
PMHS (3)
Yieldb (%)
1
2
3
4
5
6
7
0
PCy3 (5)
62
65
50
82
99
97
91
PPh3 (5)
Several experiments on more complex substrates were conductꢀ
ed in order to demonstrate the synthetic utility of these conditions
(Table 4). The corresponding nitriles were obtained from some
prototypical compounds of biological interest, such as a mimic of
the eugeroic drug modafinil (2n), an NSAID (naproxen, 2o, 100%
retention at the αꢀstereocenter), a protected sugar (2p), a betaꢀ
blocker drug (atenolol, 2q), and a drug bearing a potentially labile
Nꢀacyl indole (indomethacin, 2r). In these cases, even though
many amide substrates are relatively insoluble in common organic
solvents, we found that each compound slowly dissolves as the
silylative process proceeds. Under nearly identical reaction condiꢀ
tions, we also observed the dehydration of a urea to generate
common peptide coupling reagent N,Nꢀdicyclohexylcarbodiimide
(2s). We note that this transformation can be stopped at this stage
xantphos (5)
BINAP (5)
DMꢀBINAP (5)
DCyPE (2)
DCyPE (2)
8
a
Reaction conditions: amide (0.1 mmol), copper(II) acetate (n
mol%), ligand (1.1n mol%), silane (indicated equiv), in THF (0.1
mL) at RT for 12 h. See supporting information for additional
details. b The yield was assessed by GC analysis of the crude reacꢀ
tion mixture, using dodecane as an internal standard. 5 mol%
copper(II) acetate was used, but no additional ligand was added.
c
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since subsequent reduction of the carbodiimide group to an amiꢀ
dine is significantly slower. Finally, the reaction can be conducted
on a preparatively useful scale with 1.0 mol % catalyst loading
without need for flameꢀdried glassware or inertꢀatmosphere
glovebox equipment (Figure 2).
1
2
3
4
Table 3. Examples of CuH-Catalyzed Amide Dehydrationa
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a
a Reaction conditions: amide (0.5 or 1.0 mmol), copper(II) aceꢀ
tate (0.02 equiv), 1,2ꢀbis(dicyclohexylphosphino)ethane (0.022
equiv), dimethoxy(methyl)silane (3 equiv) in THF (1 mL) at RT
for 12 h, unless otherwise specified; see supporting information
for details. Yield represents average isolated yield of two or more
replicates. 5 equiv silane was used. At 40 °C instead of RT;
1,4ꢀdioxane (2 mL) was used instead of THF. d Yield as measured
by gas chromatography, relative to an internal standard.
Reaction conditions: amide (1.0 mmol), copper(II) acetate
(0.02 equiv), 1,2ꢀbis(dicyclohexylphosphino)ethane (0.022 equiv),
dimethoxy(methyl)silane (3 equiv) in THF (1 mL) at RT for 12 h.
Yield represents the average isolated yield of two or more repliꢀ
cates. The yield enclosed in parentheses indicates the isolated
yield of a single run wherein polymethylhydrosiloxane (PMHS, 4
equiv) was used instead of dimethoxy(methyl)silane. See supportꢀ
ing information for additional details. Toluene (1 mL) was used
instead of THF. At 50 °C instead of RT. 4 equiv silane was
used.
b
c
b
c
d
1 mol% Cu(OAc)2
O
1.1 mol% DCyPE
Ph
Ph
PMHS (4 equiv)
ꢀ No chromatography (Celite filtration)
ꢀ No flameꢀdried glassware
ꢀ No glovebox
NH2
CN
At this point, we performed some mechanistic experiments to
investigate whether our original hypothesis explained the efficienꢀ
cy of this dehydration process. We considered the low temperaꢀ
ture at which this reaction proceeds to be suggestive of a distinct
operative mechanism compared to previously reported highꢀ
temperature procedures. More specifically, we wanted a way to
directly test if we were successfully able to divert the reaction
sequence away from the problematic disilyl imidate intermediate.
In particular, as shown in Figure 3, our hypothesis requires that
the monosilyl imidate 2 be a kinetically competent intermediate
on the reaction pathway, but the disilyl imidate 3 may not be
competent under the same conditions. Noting that copper(II) salts
without additional ligands can catalyze the dehydrogenative siꢀ
lylation of acidic groups,13 but cannot catalyze the net dehydration
reaction (Table 1, entry 1), we first reacted amide 1 with either a
single equivalent of silane or a large excess (5 equiv) of silane, in
the presence of copper(II) acetate, to generate putative intermediꢀ
ates 2 and 3 respectively. We then subjected the corresponding
crude mixtures to the reaction conditions, including additional
DCyPEꢀligated catalyst. As expected, in the former case, a good
yield of product was obtained; yet, only trace product could be
detected in the latter case, which gave nearly quantitative (92%)
recovery of starting material after protic workꢀup.14
THF (1 M), RT, 12 h
Ph
99% yield
Ph
25 mmol
5.3 g
Figure 2. MultigramꢀScale Reaction at Low Catalyst Loading,
with Inexpensive PMHS as the Silane.
2 mol% Cu(OAc)2
2.2 mol% DCyPE
DMMS (3 equiv)
O
O
5 mol% Cu(OAc)2
DMMS (1 equiv)
Ph
Ph
Ph
Ph
SiMe(OMe)2
CN
NH2
N
THF (1 M), RT, 12 h
THF (1 M), RT, 12 h
H
Ph
Ph
2
87% yield (GC)
1
315.1 amu (MS)
2 mol% Cu(OAc)2
2.2 mol% DCyPE
DMMS (3 equiv)
SiMe(OMe)2
O
O
5 mol% Cu(OAc)2
DMMS (5 equiv)
Ph
CN
Ph
Ph
Ph
SiMe(OMe)2
NH2
THF (1 M), RT, 12 h
N
THF (1 M), RT, 12 h
Ph
Ph
419.2 amu (MS)
3
<10% yield (GC)
1
Figure 3. Investigation of the Role of Monoꢀ and Disilyl Imidate
Intermediates.
In summary, we have identified a functionꢀgroupꢀtolerant copꢀ
perꢀcatalyzed method for the synthesis of nitriles, which circumꢀ
vents the uncatalyzed thermal elimination step required by typical
metalꢀcatalyzed processes. Although further studies are underway
to elucidate the fundamental metalꢀligand interactions responsible
for facilitating this lowꢀbarrier elimination pathway, we believe
that this type of general process may serve as a platform for the
design of other useful, nonꢀreductive CuHꢀcatalyzed reactions.
Table 4. Further Examples of Amide Dehydrationa
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website.
Full procedures, computational details, characterization
for known and new compounds (PDF).
AUTHOR INFORMATION
8
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Corresponding Author
*Email: sbuchwal@mit.edu
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Author Contributions
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‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Research reported in this publication was supported by the Naꢀ
tional Institutes of Health (GM058160, GM122483, GM058160ꢀ
17S1). The content of this communication solely reflects the reꢀ
search and opinion of the authors and does not necessarily repreꢀ
sent the official views of the NIH. R.Y.L thanks MIT for Presiꢀ
dential Graduate Fellowships and Bristol–Myers Squibb for a
Fellowship in Synthetic Organic Chemistry. M.B. thanks Samꢀ
sung Group for a Samsung Scholarship and MIT for support
through the Undergraduate Research Opportunities Program. We
are grateful to Drs. Andy Thomas and Christine Nguyen for adꢀ
vice on the preparation of this manuscript.
REFERENCES
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Lautens, M., Eds.; Thieme: Stuttgart, 2011. Vol. 19, p. 79. (b) Compre-
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A. R.; Taylor, R. J. K., Eds.; Elsevier: Amsterdam, 2004. Vol 2.
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G., Hagedorn, F., Gelbke, H.ꢀP. Nitriles. In Ullmann’s Encyclopedia of
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Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902.
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A.; Engels, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances:
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Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563. (g) Gregory, R.
J. H. Chem. Rev. 1999, 99, 3649. (h) The Chemistry of the Cyano Group;
Rappoport, Z., Ed. Wiley: Weinheim, 1971.
3. For a recent, comprehensive overview of nitrile synthesis, see:
Larock, R. C.; Yao, T. Formation of Nitriles, Carboxylic Acids, and Deꢀ
rivatives by Oxidation, Substitution, and Addition. In Comprehensive
Organic Transformations, 3rd ed.; Wiley, 2018.
4. For selected modern methods of preparing nitriles, see, along with
ref. 6, the following: (a) Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu, G. J.
Am. Chem. Soc. 2017, 139, 15632. (b) McManus, J. B.; Nicewicz, D. A. J.
Am. Chem. Soc. 2017, 139, 2880. (c) Shi, S.; Szostak, M. Org. Lett. 2017,
19, 3095. (d) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.;
Stahl, S. S.; Liu, G. Science 2016, 353, 1014. (e) Fang, X.; Yu, P.; Moranꢀ
di, B. Science 2016, 351, 832. (f) Wu, Q.; Luo, Y.; Lei, A.; You, J. J. Am.
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2016, 6, 5989. (h) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015, 17, 202.
(i) Jagadeesh, R. V.; Junge, H.; Beller, M. Nat. Commun. 2014, 5, 4123.
(j) Yu, L.; Li, H.; Zhang, X.; Ye, J.; Liu, J.; Xu, Q.; Lautens, M. Org. Lett.
2014, 16, 1346. (k) Lambert, K. M.; Bobbitt, J. M.; Eldirany, S. A.; Wiꢀ
berg, K. B.; Bailey, W. F. Org. Lett. 2014, 16, 6484. (l) Shen, T.; Wang,
T.; Qin, C.; Jiao, N. Angew. Chem. Int. Ed. 2013, 52, 6677. (m) Yin, W.;
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thesis 2013, 45, 2155. (p) Enthaler, S.; Weidauer, M.; Schroeder, F. Tet-
8. For early examples establishing the utility of hydrosilanes in convertꢀ
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Tetrahedron Lett. 2005, 46, 2037. (b) Lipshutz, B. H;, Servesko, J. M.;
Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273. (c)
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9. For copperꢀcatalyzed transformations for which DCyPE is an effecꢀ
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1
2
3
4
10. Commercial PMHS can be obtained in highly variable quality, in
several different chain lengths, and with a choice of terminal groups. We
evaluated several batches of PMHS from different vendors and of differꢀ
ent ages, and the model reaction was successful in all cases. However, the
yields can vary by up to 20% between batches without obvious indication
of cause, unless a larger excess (4 equiv) of PMHS is employed. In the
interest of maximum reproducibility, we chose to use DMMS as the silane
in the substrate scope studies. The use of PMHS is demonstrated on severꢀ
al representative substrates in Table 2, and on large scale in Figure 2.
11. For this study, we obtained DMMS from TCI America, and the maꢀ
terial was stored without further purification in the refrigerator at 0 °C for
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1
up to 4 months after opening. H NMR analysis indicated no detectable
decomposition, including methanol formation by hydrolysis. Even if slight
decomposition should occur, minimal detrimental effect is expected since
the addition of 0.1 equiv of either water or MeOH did not significantly
alter the yield of the model reaction. Furthermore, several batches of
DMMS of different age and storage condition were employed with miniꢀ
mal variation in yield.
12. For detailed information about the safe handling of DMMS, please
see the supporting information.
13. Alcoholysis and aminolysis of Si–H bonds is known to be catalyzed
by a variety of metals and metal salts; for instance, see: Lukevics, E.;
Dzintara, M. J. Organomet. Chem. 1985, 295, 265 and references therein.
14. To confirm that the failure of the second experiment is due to the
conversion of 1 to an inactive species, rather than, for instance, decompoꢀ
sition of the catalyst in the presence of some detrimental contaminant, we
added a small amount of a second primary amide to 3 and conducted the
CuHꢀcatalyzed dehydration reaction. The unsilylated amide was fully
converted to the corresponding, while 3 was not converted to the correꢀ
sponding nitrile:
nꢀC11H23CONH2 (20 mol%)
2 mol% Cu(OAc)2
2.2 mol% DCyPE
DMMS (3 equiv)
SiMe(OMe)2
O
Ph
Ph
Ph
SiMe(OMe)2
CN
nꢀC11H23CN
+
N
THF (1 M), RT, 12 h
Ph
<10% yield (GC) 90% yield (GC)
3
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should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem,
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1 mol% Cu(OAc)2
1.1 mol% DCyPE
PMHS (4 equiv)
‡
R3Si
O
Ph
Ph
O
CuLn
Ph
NH2
CN
via Ph
N
THF (1 M), RT, 12 h
Ph
Ph
99% yield
25 mmol
5.3 g
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