Towards nitrile-substituted cyclopropanes-a slow-release protocol for safe and scalable applications of diazo acetonitrile

Article abstract of DOI:10.1039/c7gc00602k

Diazo acetonitrile has long been neglected despite its high value in organic synthesis due to a high risk of explosions. Herein, we report our efforts towards the transient and safe generation of this diazo compound, its applications in iron catalyzed cyclopropanation and cyclopropenation reactions and the gram-scale synthesis of cyclopropyl nitriles.

Full text of DOI:10.1039/c7gc00602k

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Towards nitrile-substituted cyclopropanes – a slow-release
protocol for safe and scalable applications of diazo acetonitrile
Received 00th January 20xx,
Accepted 00th January 20xx
Katharina J. Hock, Robin Spitzner, and Rene M. Koenigs*
DOI: 10.1039/x0xx00000x
www.rsc.org/
13
)
Diazo acetonitrile has long been neglected despite its high value in Levomilnacipran
(
5
and 5HT2C agonist 614 contain
a
organic synthesis due to a high risk of explosions. Herein, we prominent trans- methylamino cyclopropane.
report our efforts towards the transient and safe generation of
this diazo compound, its applications in iron catalyzed
cyclopropanation and cyclopropenation reaction and the gram-
scale synthesis of cyclopropyl-nitriles.
The chemistry of diazo compounds has made remarkable
advances in the past years. However, the synthetic utility of
small, reactive diazo compounds has long been neglected,
although they possess great potential for the highly efficient
and concise construction of small functional molecules.1,2
In particular, diazo acetonitrile represents
a very close
analogue of ethyl diazo acetate and is almost completely
unexplored from a synthetic perspective,3-7 although it was
first described by Curtius in 1898.3 Over the past decades there
is only few reports on diazo acetonitrile, which can be
attributed to the high risk of explosions when handling diazo
acetonitrile. Phillips and Champion reported serious
explosions, while handling this particular diazo compound.4a
In the context of our ongoing interest in small and reactive
diazo compounds,8 we decided to investigate diazo acetonitrile
Figure 1. Nitrile- and methylamino- cyclopropanes.
Although many applications of cyclopropyl nitriles in
pharmaceutical research are known, current state-of-the-art
synthesis protocols require tedious multi-step synthesis, which
is far from being atom-economical. Alternatively, metal-
mediated atom transfer radical additions15 or Corey-
Chaykovsky cyclopropanation reactions are reported, though
poor diastereomeric excess was obtained.11 There is only a
single report in the literature investigating diazo acetonitrile as
a preformed reagent, though it suffers from reaction safety,
low yields and diastereoselectivity.5d To the best of our
knowledge, no direct and thus atom-efficient, safe one-step
synthesis of cyclopropyl nitriles starting from simple and
readily available olefins and bench-stable amines has been
reported to date.
in
cyclopropanation
reactions.
The
corresponding
cyclopropanes represent an important structural class with
very interesting biological activity and are currently used as
9
Cathepsin C inhibitors (
receptor modulators (
1
)
or as positive allosteric NMDA
2
).10 Interestingly, one of the most
simple cyclopropyl nitriles, namely 1-carbonitrile-2-phenyl-
cyclopropane (3a), is used as a fragrance.11
Moreover, the nitrile can be readily reduced to provide
methylamino-substituted cyclopropanes, which are highly
demanded in drug discovery. For example, Tasimelteon (4)
contains a central methylamino substituted cyclopropane.12
This structural motif can be readily obtained from the
corresponding nitrile-substituted cyclopropane. Similarly,
Recently, the in-situ generation of diazo compounds from
amines and organic2g,8,16 or inorganic nitrite6,17 sources
attracted the interest of many groups. In particular, phase-
transfer protocols proved as a valuable method to prepare
different acceptor-only substituted diazo compounds. In 2015,
Mykhailiuk reported a first paper on the in-situ generation of
diazo acetonitrile in a one-pot dipolar cycloaddition reaction.6
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of organic solvent proved to be inferior in terms of product
yield (table 1, entry 5). Interestingly, upon addition of a small
amount of dichloromethane to the reaction mixture, and thus
in a phase transfer protocol with a highly concentrated organic
layer, the reaction product was formed in very good isolated
yield (table 1, entry 8 and 9).
With the optimal reaction conditions in hand, we then
investigated the substrate scope using different styrene
derivatives. Different electron-donating and electron-
withdrawing substituents and substitution patterns at the
aromatic ring were investigated and the corresponding
cyclopropanes could be isolated in very good yield with good
diastereoselectivity using 1 or 3 mol-% FeTPPCl as catalyst.
Similarly, vinyl-substituted naphthalenes (table 2, entry 3l and
3m) provided the desired cyclopropanation product in good
yield and diastereoselectivity. Further investigations
concentrated on sulfur-containing heterocycles, which reacted
smoothly to the nitrile-substituted cyclopropane product. It
should be noted, that 4-vinyl pyridine did not provide the
Scheme 1. Catalytic synthesis of cyclopropane nitriles.
Thus, we started our investigations by examining the on water
generation of diazo acetonitrile and
a
subsequent
cyclopropanation reaction with styrene. We hypothesized that
slow addition of sodium nitrite will result in a slow and
continuous release of diazo acetonitrile in the reaction
mixture. This slow-release protocol would allow the transient
formation of highly reactive and explosive diazo acetonitrile
and thus minimize risks while working with this hazardous
reagent, when comparing to one-pot batch reactions.6 Under
those conditions, we probed different metal catalysts (e.g.
Ru(TPP)CO, Co(salen), Rh2OAc4) and were delighted to observe
the desired cyclopropane in acceptable yield, although no
desired reaction product.
Table 2. Survey of different additives and reaction conditions.
significant diastereoselectivity was achieved.18, 19
Table 1. Survey of different additives and reaction conditions.
entry
solvent
additive
d.r.
yield
1
2
water
water
6:1
6:1
4:1
6:1
6:1
6:1
6:1
6:1
6:1
70
56
35
42
40
61
65
81
83
DMAP (0.1 eq)
3
4[b]
water
N-Me imidazole (0.1 eq)
water
5
CHCl3 : H2O (30:1)
water
6
PhMe (100µL)
CHCl3 (100 µL)
DCM (100 µL)
DCM (100 µL)
7
water
8
9[c]
water
water
reaction conditions: 0.4 mmol styrene, 1-3 mol-% of FeTPPCl,
2
eq
aminoacetontrile hydrochloride were dissolved in 1 mL of solvent indicated.
NaNO2 (3 eq) dissolved in 1 mL water was added over a period of 10 h at rt; the
resulting mixture was stirred for another 4 h at rt; yields refer to the trans
product after column chromatography; the d.r. was determined from the crude
reaction mixture by 1H-NMR; [b] at 0°C; [c] 3 mol-% FeTPPCl.
If FeTPPCl (table 1) is used as catalyst,
a
good
diastereoselectivity of 6:1 (trans:cis) was observed and the
desired cyclopropane could be isolated in good yield. Different
additives such as DMAP or N-methyl imidazole were tested,
though no increase in diastereoselectivity or yield was
observed. Similarly, lower reaction temperatures did not
provide satisfying results (table 1, entry 4). To improve the
yield, we next tested phase transfer protocols: large amounts
reaction conditions: 0.4 mmol styrene (7a-o), 1-3 mol-% FeTPPCl,
2 eq
aminoacetonitrile hydrochloride (8) were dissolved in H2O/CH2Cl2 (1 mL /
100 µL). NaNO2 (3 eq) dissolved in 1 mL water was added over a period of 10 h at
rt; the resulting mixture was stirred for another 4 h at rt; reported yields refer to
the trans product after column chromatography; the d.r. was determined from
the crude reaction mixture by 1H-NMR; [a] using 3 mol-% of catalyst.
2 | J. Name., 2012, 00, 1-3
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In further studies we probed a range of different α-methyl unsatisfactory yield and diastereoselectivity (yield by 19F-NMR
styrenes, which were readily converted to the corresponding <10%, d.r. 1:1). However, if the more reactive Fe(F20TPP)Cl19
cyclopropyl nitriles with good diastereoselectivity and high catalyst was used, α-trifluoromethyl styrene was readily
yield. Both electron-donating and electron-withdrawing converted to the corresponding trifluoromethyl-substituted
substituents were well tolerated. Similarly, the effect of the cyclopropane
12c
with
good
yield
and
little
substitution pattern of the aromatic ring was investigated, diastereoselectivity. It should be noted that under the present
though only a minor influence was observed. Interestingly, reaction conditions, trans-β-methyl styrene, indene or
different carbocycles as well as oxygen and sulfur-containing allylbenzene were investigated, though no reaction product
heterocycles reacted efficiently to yield the hetero- and was obtained.
carbocyclic cyclopropanes (10g-l).
Table 4. Substrate scope of different α-methyl styrenes.
Table 3. Substrate scope of different α-methyl styrenes.
reaction conditions: 0.4 mmol styrene (11a-c),
3 mol-% FeTPPCl, 2 eq
aminoacetonitrile hydrochloride were dissolved in H2O/CH2Cl2 (1 mL / 100 µL).
NaNO2 (3 eq) dissolved in 1 mL water was added over a period of 10 h at rt; the
resulting mixture was stirred for another 4 h at rt; reported yields refer to the
trans product after column chromatography; the d.r. was determined from the
crude reaction mixture by 1H-NMR.
Furthermore, we investigated cyclopropenation reactions
using phenyl-propyne (13) and Rh2esp2 as catalyst.19 To our
delight, we were able to isolate the desired cyclopropene 14 in
good yield (scheme 2). Notably, FeTPPCl did not provide the
desired cyclopropene.
reaction conditions: 0.4 mmol styrene (9a-l),
3 mol-% FeTPPCl, 2 eq
aminoacetonitrile hydrochloride were dissolved in H2O/CH2Cl2 (1 mL / 100 µL).
NaNO2 (3 eq) dissolved in 1 mL water was added over a period of 10 h at rt; the
resulting mixture was stirred for another 4 h at rt; reported yields refer to the
trans product after column chromatography; the d.r. was determined from the
crude reaction mixture by 1H-NMR.
Scheme 2. Cyclopropenation reaction with Rh2esp2.
The scale-up of transformations using diazo compounds is of
particular interest for potential applications involving this class
of highly reactive reagents. In particular, diazo acetonitrile has
been demonstrated to possess a high risk of explosions and
the safe and routine application of this reagent is of primary
importance for its use. We therefore decided to evaluate the
scalability of this slow-release protocol and were delighted to
observe that the gram-scale synthesis of fragrance 3a
proceeded smoothly using 1 mol-% of catalyst and 86%
isolated yield. If the more reactive Fe(F20TPP)Cl catalyst was
used in this transformation, the catalyst loading can be
reduced to as low as 0.03 % and the desired cyclopropyl nitrile
3a was isolated in good yield.
Further investigations concentrated on different α-substituted
styrenes using iron catalysts. α-ethyl styrene, diphenyl
ethylene readily provided the desired cyclopropanation
product in moderate to good yield.
We then hypothesized that electron-poor and thus weakly
nucleophilic α-trifluoromethyl styrene derivatives are highly
interesting substrates for the construction of trifluoromethyl-
and nitrile disubstituted cyclopropanes. To date, there is only
one report claiming α-trifluoromethyl styrene in
a
cyclopropanation reaction using a dimeric Fe(salen) complex
as catalyst.20 Against this background, we became interested in
examining our protocol in this particular transformation.
Notably, FeTPPCl was almost inactive in the cyclopropanation
reaction provding the desired reaction product 12c only in
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Roelants and A. Bruylants, Tetrahedron, 1978, 34, 2229-
2232; d) J. Hooz and S. Linke, J. Am. Chem. Soc., 1968, 90
,
6891-6892; d) D. T. Witiak, and M. C. Lu, J. Org. Chem., 1970,
35, 4209.
5
For an overview on diazo acetonitrile in recent years: a) Z.
Yang, K.-I. Son, S. Li, B. Zhou and J. Xu, Eur. J. Org. Chem.,
2014, 6380-6384; c) C. V. Galliford and K. A. Scheidt, J. Org.
Chem., 2007, 72, 1811-1813; d) Y. Ferrand, P. Le Maux and G.
Simmoneaux, Tetrahedron: Asymmetry, 2005, 16, 3829-
3836; e) F.-X. Felpin, E. Doris, A. Wagner, A. Valleix, B.
Rousseau, and C. Mioskowski, J. Org. Chem., 2001, 66, 305.
P. K. Mykhailiuk, Eur. J. Org. Chem., 2015, 7235-7239.
references on nitrile-substituted donor-acceptor diazo
compounds: a) J. R. Denton, K. Cheng and H. M. L. Davies,
Chem. Commun., 2008, 1238-1240; b) J. H. Hansen, B. T.
Parr, P. Pelphrey, Q. Jin, J. Autschbach and H. M. L. Davies,
Angew. Chem. Int. Ed., 2011, 50, 2544-2548; c) J. F. Briones
and H. M. L. Davies, Org. Lett., 2011, 13, 3984-3987; d) F. G.
6
7
Scheme 3. Gram-scale synthesis and derivatization of the nitrile cyclopropane.
Reduction of the cyclopropyl-nitrile provides a simple and
high-yielding access to trans-configured cyclopropyl
methylamines (15) that are key building blocks in drug
discovery and used as 5HT2c agonists.
Adly, M. G. Gardiner and A. Ghanem, Chem. Eur. J., 2016, 22
3447-3461; e) R. R. Singh, S. K. Pawar, M.-J. Huang and R.-S.
Liu, Chem. Commun., 2016, 52, 11434-11437.
a) K. J. Hock, L. Mertens and R. M. Koenigs, Chem. Commun.,
2016, 52, 13783-13786; b) K. J. Hock, L. Mertens, F. K. Metze,
,
8
9
In summary, we have established a protocol that allows for the
a diastereoselective, catalytic one-step synthesis of high-
valued nitrile-substituted cyclopropanes and cyclopropenes.
This slow-release protocol enables safe and scalable
applications of highly explosive diazo acetonitrile and opens up
new synthetic opportunities using this reagent. We were able
C. Schmittmann, and R. M. Koenigs, Green Chem., 2017, 22
905.
,
J. Pedersen, C. Lauritzen, 2012, WO2012130299 (Prozymex
A/S).
10 M. Volgraf, B. D. Sellers, Y. Jiang, G. Wu, C. Q. Ly, E.
Villemure, R. M. Pastor, P.-W. Yuen, A. Lu, X. Luo, M. Liu, S.
Zhang, L. Sun, Y. Fu, P. J. Lupardus, H. J. A. Wallweber, B. M.
Liederer, G. Deshmukh, E. Plise, S. Tay, P. Reynen, J.
Herrington, A. Gustafson, Y. Liu, A. Dirksen, M. G. A. Dietz, Y.
Liu, T.-M. Wang, J. E. Hanson, D. Hackos, K. Scearce-Levie
and J. B. Schwarz, J. Med. Chem., 2016, 59, 2760-2779.
11 A. P. S. Narula, E. M. Arruda, A. J. Janczuk and F. T. Schiet,
2006, US20060287204 (International Flavors and Fragrances
Inc.)
to demonstrate its synthetic potential on
a gram-scale
synthesis of vital building blocks for drug discovery.
Notes and references
Funded by the Excellence Initiative of the German federal and
state governments. The authors gratefully thank the Fonds der
Chemischen Industrie for generous support (Sachkostenbeihilfe).
12 a) A. C. Flick, H. X. Ding, C. A. Leveretti, R. E. Kyne, K. K-C. Liu,
S. J. Fink and C. J. O’Donnell, Bioorg. Med. Chem., 2016, 24,
1937-1980; b) J. D. Catt, G. Johnson, D. J. Keavy, R. J.
Mattson, M. F. Parker, K. S. Takaki and J. P. Yevich, 1999,
US5856529 (Bristol-Myers Squibb).
1
Selected review articles on diazo compounds: a) M. P. Doyle,
M. A. McKervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, Wiley,New York,
1998; b) A. Ford, H. Miel, A. Ring, A. N. Slattery, A. R.
Maguire and M. A. McKervey, Chem. Rev., 2015, 115, 9981-
10080; c) L. Mertens and R. M. Koenigs, Org. Biomol. Chem.,
2016, 14, 10547-10556; d) H. U. Reissig and R. Zimmer,
Chem. Rev., 2003, 103, 1151-1196; e) H. M. L. Davies and R.
E. J. Beckwith, Chem. Rev., 2003, 103, 2861-2903; f) M. P.
Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010,
110, 704-724; g) A. Padwa, Chem. Soc. Rev., 2009, 38, 3072-
3081; h) H. M. L. Davies and J. R. Denton, Chem. Soc. Rev.,
2009, 38, 3061-3071; i) H. Lebel, J.-F. Marcoux, C. Molinaro
and A. B. Charette, Chem. Rev., 2003, 103, 867-872.
13 a) P. M. Farina, R. I. Rodriguez Curiel, S. Maiorana, A. Bianchi,
F. Colombo and G. Timpano, 2015, WO2015092502
(Laboratorio Chimico Internazionale), b) S. Shuto, S. Ono, Y.
Hase, N. Kamiyama and A. Matsuda, Tetrahedron Letters,
1996, 37, 641-644; c) M. Doyle and W. Hu, Adv. Synth. Catal.,
2001, 343, 299-302.
14 J. Cheng, J. D. McCorvy, P. M. Giguere, H. Zhu, T. Kenakin, B.
L. Roth and A. P. Kozikowski, J. Med. Chem., 2016, 59, 9866-
9880.
15 K. Thommes, G. Kiefer, R. Scopelliti and K. Severin, Angew.
Chem. Int. Ed., 2009, 48, 8115-8119.
16 P. K. Mykhailiuk, Angew. Chem. Int. Ed., 2015, 54, 6558.
17 a) A G. M. Barrett, D. C. Braddock, I. Lenoir and H. Tone, J.
Org. Chem., 2001, 66, 8260-8263; b) R. P. Wurz and A. B.
2
Selected references: a) S. T. R. Mueller and T. Wirth,
ChemSusChem, 2015, 8, 245-250; b) B. J. Deadman, S. G.
Collins and A. R. Maguire, Chem. Eur. J., 2015, 21, 2298-2308;
c) M. Movsisyan, E. I. P. Delbeke, J. K. E. T. Berton, C.
Battilocchio, S. V. Ley and C. V. Stevens, Chem. Soc. Rev.,
2016, 45, 4892-4928; d) P. K. Mykhailiuk, Angew. Chem. Int.
Ed., 2015, 54, 6558-6561; e) B. Morandi and E. M. Carreira,
Science, 2012, 335, 1471-1474; f) J. Kaschel, T. F. Schneider
and D. B. Werz, Angew. Chem. Int. Ed., 2012, 51, 7085-7086;
g) L. Mertens, K. J. Hock and R. M. Koenigs, Chem. Eur. J.
2016, 22, 9542-9545.
Charette, Org. Lett., 2002,
M. Carreira, Angew. Chem. Int. Ed., 2010, 49, 938-941; d) B.
Morandi, J. Cheang and E. M. Carreira, Org. Lett., 2011, 13
4, 4531-4533; c) B. Morandi and E.
,
3080-3081; e) P. K. Mykhailiuk, Chem. Eur. J., 2014, 20, 4942-
4947; f) E. Y. Slobodyanyuk, O. S. Artamonov, O. V. Shishkin
and P. K. Mykhailiuk, Eur. J. Org. Chem. 2014, 2487-2495.
18 for details see supporting information.
19 TPP = 5,10,15,20-Tetraphenyl-21H,23H-porphine, F20TPP =
5,10,15,20-Tetrakis(pentafluorophenyl)-21H,23H-porphyrin,
esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid.
3
4
T. Curtius, Chem. Ber., 1898, 31, 2489-2492.
Selected articles on diazo acetonitrile: a) D. D. Phillips and W.
C. Champion, J. Am. Chem. Soc., 1956, 78, 5452; b) M. J. S.
Dewar and R. Pettit, J. Chem. Soc., 1956, 2026-2029; c) F.
20 S. K. Eduiji and S. T. Nguyen, Organometallics, 2003, 22
3374-3381.
,
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Applications of diazo acetonitrile in cyclopropa(e)nation reactions are realized in a slow-release protocol with bench-stable reagents. The
cyclopropyl nitriles are obtained in one-step in good diastereoselectivity on gram-scale providing an efficient entry into this class of fragrances and
drug-like molecules.