Matched Coupling of Propargylic Carbonates with Cyclopropanols

Article abstract of DOI:10.1021/acs.orglett.7b03637

The ring opening-coupling reaction of cyclopropanols with propargylic carbonates affording synthetically attractive allenyl ketones has been developed. The mechanism involves the ligand-exchange reaction of in situ formed allenyl palladium methoxide with cyclopropanols followed by carbon-carbon bond cleavage and reductive elimination. The reactions proceeded smoothly under mild reaction conditions with Pd(0)/XPhos catalysis in the absence of any external base and displayed a wide scope and application to a steroidal skeleton. The efficiency of chirality transfer and synthetic utility of the allene products have also been demonstrated.

Full text of DOI:10.1021/acs.orglett.7b03637

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Matched Coupling of Propargylic Carbonates with Cyclopropanols
†
,†
‡
,†,‡
Penglin Wu, Minqiang Jia,* Weilong Lin, and Shengming Ma*
†Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Road, Shanghai
00433, P. R. China
2
‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China
*
S Supporting Information
ABSTRACT: The ring opening−coupling reaction of cyclopropanols with propargylic carbonates affording synthetically
attractive allenyl ketones has been developed. The mechanism involves the ligand-exchange reaction of in situ formed allenyl
palladium methoxide with cyclopropanols followed by carbon−carbon bond cleavage and reductive elimination. The reactions
proceeded smoothly under mild reaction conditions with Pd(0)/XPhos catalysis in the absence of any external base and
displayed a wide scope and application to a steroidal skeleton. The efficiency of chirality transfer and synthetic utility of the allene
products have also been demonstrated.
he transition-metal-catalyzed coupling reaction of prop-
argylic alcohol derivatives with preformed organometallic
C bond cleavage reaction with the oxidative addition of
propargylic carbonates with palladium, the intrinsic readily
occurring β-H elimination affording α,β-unsaturated enone B
together with the corresponding reductive elimination product
allene C, and the possible formation of regioisomeric product
alkyne D (Scheme 1B). Here, we report our recent results on Pd-
catalyzed efficient and highly selective synthesis of allenyl
ketones.
T
reagents such as organomagnesium, aluminum, zinc, borane, and
silane reagents have been extensively studied for the synthesis of
1
−4
either alkynes and/or allenes
(Scheme 1A). We envisioned
application to cyclopropanols, which are readily available from
Ti-catalyzed reaction of carboxylates with ethylmagnesium
5
,6
bromide, as an equivalent to organometallic reagents to couple
with propargylic carbonates forming intermediate A to afford
Cyclopropanol 1a and propargylic carbonate 2a were taken as
the model substrates to test our hypothesis. After some trial and
error, toluene was the solvent of choice for this transformation.
Subsequently, different types of phosphine ligands were
screened. Unfortunately, Pd(dba) and PPh provided merely
7
allenyl ketone products. The challenges are the match of the C−
Scheme 1. Different Coupling Protocols and 3,4-Allenyl
Ketone Synthesis
2
3
1
3% yield of the desired allene product 3aa, and the B-type of β-
H elimination product enone 4′ and C-type of allene 3aa′ were
observed as the major products. In addition, an unexpected ring-
opening−protonolysis product, ethyl benzyl ketone 4, was also
formed (Table 1, entry 1).
When other ligands, such as PCy , rac-BINAP, LB-Phos, and
3
Gorlos-Phos, were used, the substrate 2a was recovered with
various amounts of the byproducts 3aa′, 4, and 4′ (Table 1,
entries 2−5). To our delight, when SPhos was used as ligand, the
corresponding allene product was generated in 58% yield,
although 3aa′ was also formed in 20% yield (Table 1, entry 6).
Furthermore, changing ligand to XPhos provided 3aa in 78%
Received: November 22, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope Referred to Cyclopropanols
b
b
b
yield
yield
recovery
entry
[Pd]
ligand
PPh3
(3aa, %) (3aa′/4/4′, %)
(2a, %)
c
1
Pd(dba)2
Pd(dba)2
Pd(dba)2
13
0
54/5/51
5/6/<3
0/4/<3
0
87
62
c
2
PCy3
c
3
rac-
BINAP
0
c
4
Pd(dba)2
Pd(dba)2
LB-Phos
0
0
27/6/8
9/8/13
61
67
c
5
Gorlos-
Phos
c
6
Pd(dba)2
Pd(dba)2
Pd(dba)2
SPhos
XPhos
XPhos
58
78
73
73
54
84
59
20/3/6
5/4/<3
10/13/4
10/15/<3
4/12/6
6/4/8
0
0
7
d
8
0
9
Pd(OAc)2 XPhos
Pd(TFA)2 XPhos
0
1
1
1
0
26
0
e
1
Pd(dba)2
XPhos
f
2
Pd(dba)2
XPhos
5/5/8
22
a
Reaction conditions: 1a (0.24 mmol), 2a (0.20 mmol), [Pd] (5.0 mol
b
a
%
), ligand (8.5 mol %), in solvent (1.0 mL) at 50 °C. NMR yield
Reaction conditions: 1 (1.2 mmol), 2a or 2b (1.0 mmol), Pd(dba)2
c
with CH Br as the internal standard. [Pd] (5.0 mol %), ligand (10.0
mol %) was used. Cs CO (1.5 equiv) was added. [Pd] (2.5 mol %),
XPhos (5.0 mol %) was used. 1a (0.48 mmol), 2a (0.40 mmol), [Pd]
(2.5 mol %), and XPhos (5.0 mol %) in toluene (5.0 mL) at 50 °C.
2
2
d
e
b
Pd(dba) (5.0 mol %) and XPhos (8.5 mol %) were used.
2
3
2
f
(
1.0 mol %), XPhos (2.0 mol %), in toluene (2.0 mL) reacted for 6 h.
yield, and the formation of byproducts 3aa′, 4, and 4′ can be
suppressed to a very low level (Table 1, entry 7). Control
experiments showed that Cs CO could not improve either the
2
3
yield or selectivity of the reaction (Table 1, entry 8). The results
with Pd(OAc) and Pd(TFA) were worse (Table 1, entries 9
2
2
Figure 1. ORTEP representation of 3ea.
and 10). Finally, the loading of Pd(dba) and XPhos may be
2
reduced to 2.5 and 5 mol %, which even provided a slightly higher
yield of 3aa with a similar selectivity (Table 1, entries 11 and 12).
It should be noted that D-type alkyne product was NOT formed
in all cases.
afford the fully substituted allene products 3ak and 3al; however,
the reaction conditions had to be reengineered: K PO ·3H O
3
4
2
should be applied and the reaction should be conducted at 80 °C.
2
With the optimized reaction conditions in hand (Table 1,
entry 11), the generality of this reaction with the scope of
differently substituted cyclopropanols was investigated, and the
results are summarized in Scheme 2. Different substituents, such
as Me and synthetically useful MeO, Cl, and Br on the benzyl
group could be tolerated, providing the corresponding 3,4-allenyl
ketone products 3aa−ea in 56−74% yields. The X-ray structure8
of 3ea confirmed the allene structure unambiguously (Figure 1).
Phenoxymethyl and 4-Cl- or 4-MeO-substituted aryl groups all
worked smoothly to provide the final products 3fa, 3ga, and 3hb
When R = H, the corresponding disubstituted allene product
3an was also obtained albeit in a very low yield (20%).
Since some allenes bearing steroidal skeleton have been
9
showing pharmacological activities, cyclopropanol bearing a
steroid unit 1l was applied under the standard reaction
conditions. To our delight, the reaction with two representative
propargylic carbonates 2a and 2d worked smoothly to provide
the corresponding allene products 3la and 3ld in high yields
(Scheme 4).
Furthermore, we studied the efficiency of central to axial
chirality transfer by applying optically active chiral propargylic
carbonates (R)-2e, (R)-2g and (R)-2m (Scheme 5). The
corresponding chiral allenes were generated smoothly with
high er. The absolute configuration of the product was
determined by X-ray crystal structure of enantiopure (R)-3am
1
in 71−72% yields. R may also be different alkyl groups, such as
PhCH CH , n-hexyl, or cyclohexyl, delivering the desired allene
2
2
products 3ia−ka and 3jb in 70−74% yields.
Subsequently, different propargylic carbonates were also
2
investigated with cyclopropanol 1a (Scheme 3). R may be
10
different alkyl groups such as n-butyl, n-hexyl, and PhCH CH2
(Figure 2).
2
(
3ab−ad, 76−81% yields). Different functional groups such as
The potential of this reaction was further demonstrated on
gram-scale synthesis of the allene product 3db in 75% yield. This
allene product 3db may be subjected to various types of
transformations, such as reduction of the ketone group with
CC bond, chloro, ketone, ester, and cyano groups may all be
2
3
incorporated into R and R to provide the final products 3ae−aj
in 55−79% yields. In addition to these secondary propargylic
carbonates, tertiary propargylic carbonates may also be applied to
NaBH providing the secondary alcohol 5, 1,2-addition of the
4
B
DOI: 10.1021/acs.orglett.7b03637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope Referred to Propargylic
Carbonates
Scheme 5. Chiral Allene Synthesis via Chirality Transfer
a
a
Reaction conditions: 1a (1.2 mmol), 2 (1.0 mmol), Pd(dba) (2.5
2
mol %), and XPhos (5.0 mol %) in toluene (5.0 mL) at 50 °C.
b
c
Pd(dba) (5.0 mol %) and XPhos (8.5 mol %) were used. 1a (1.0
2
d
mmol) was used. Pd(dba) (2.5 mol %), XPhos (5.0 mol %), and
2
Figure 2. ORTEP representation of (R)-3am.
K PO ·3H O (1.0 equiv) in toluene (5.0 mL) at 80 °C.
3
4
2
Scheme 6. Mechanistic Studies
Scheme 4. Synthesis of Allenes Containing a Steroidal
Skeleton
ketone group with EtMgBr or alkynyl lithium reagent generating
the tertiary alcohols 6 and 7, and reductive amination yielding
allenyl amine 8. The one-pot reduction-Au(I)-catalyzed
cyclization was also conducted providing the trisubstituted
tetrahydrofuran derivative 12 in a decent yield (Scheme S1 in the
SI file).
reason for the high selectivity of allene over alkyne (Scheme 6, eq
2).
To shed some light on the reaction mechanism, several control
experiments were carried out (Scheme 6). First, when cyclo-
propanol 1a was submitted to the standard conditions, 1a was
recovered in 84% yield together with 6% of ring opening
protonolysis product 4, and β-H elimination product 4′ was not
observed, indicating that most likely the reaction did not start
with 1a (Scheme 6, eq 1). Second, when carbonate 2a was treated
with ethanol instead of cyclopropanol 1a, both alkyne 9a and
allene 3aa′ were formed respectively, as a mixture, indicating the
unique effect of the cyclopropanols on the high selectivity for the
exclusive formation of allene. Although a very slow reaction was
observed when tert-butyl alcohol was used, both 9a and 3aa′ were
Finally, the coupling of propargylic acetate 10a with 1a was
found to be not only quite sluggish but also to yield the related
allene product 3aa in only 26% NMR yield together with 35%
NMR yield of ketone 4 and 24% of 10a, which highlighted the
importance of the carbonate for the high selectivity of this
coupling reaction matched reactivity of carbonates with the ring-
opening reaction of cyclopropanols (Scheme 6, eq 3).
On the basis of these results and the stereochemical outcome
of the chirality transfer shown in Scheme 5, a plausible
mechanism is proposed (Scheme 7): S 2′-type anti-oxidative
N
addition of Pd(0) with propargylic carbonate 2 would provide, by
eliminating a molecule of CO , the allenyl palladium methoxide
2
1
detected with a similar ratio as with EtOH as judged by H NMR
intermediate I, which would undergo ligand exchange with
cyclopropanol 1 providing the intermediate II. Subsequent ring
analysis and isolation; thus, steric effects were not the major
C
DOI: 10.1021/acs.orglett.7b03637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 7. Proposed Mechanism
ACKNOWLEDGMENTS
Financial support from the National Basic Research Program
2015CB856600) and the National Natural Science Foundation
■
(
of China (21502020) is greatly appreciated. We thank Jing Zhou
in this group for reproducing the results of 3fa in Scheme 2, 3al in
Scheme 3, and (R)-3cg in Scheme 5.
REFERENCES
■
(
1) For reviews: (a) Modern Allene Chemistry; Krause, N., Hashmi, A.
S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2. (b) Ma, S. Eur. J.
Org. Chem. 2004, 1175.
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(a) Matsuda, I.; Komori, K.; Itoh, K. J. Am. Chem. Soc. 2002, 124, 9072.
(b) Ardolino, M. J.; Morken, J. P. J. Am. Chem. Soc. 2012, 134, 8770.
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(3) For selectivitity control in such reactions, see: Ma, S.; Wang, G.
Angew. Chem., Int. Ed. 2003, 42, 4215.
opening reaction of the three-membered cycle involving a β-C
elimination would yield intermediate III, which would undergo
reductive elimination to deliver the final product 3 and
regenerate the Pd(0) species to complete the catalytic cycle.
We reason that the steric bulkiness of the ligand (XPhos)
prevents intermediate III from β-H elimination and facilitates the
subsequent reductive elimination, thus, avoiding the formation of
B- and C-type of products shown in Scheme 1.
In conclusion, a palladium-catalyzed highly selective and
efficient synthesis of allenyl ketones via the matched oxidative
addition of propargylic carbonates with Pd(0) and the ring
opening of cyclopropanols has been developed. The reaction
features mild reaction conditions and a wide substrate scope
without using any air sensitive metal reagents or external base,
allowing the efficient introduction of the allene unit into useful
organic skeleton including even the steroidal skeleton. The high
efficiency of chiral transfer and synthetic utility of the 3,4-allenyl
ketone products were also demonstrated.
(4) For selected examples on selective formation of allenes, see:
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(b) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer, P.
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M. Chem. Commun. 1997, 2083. (e) Riveiros, R.; Rodriguez, D.; Sestelo,
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Gau, H.-M. Eur. J. Org. Chem. 2014, 7916. (i) Zhao, T. S. N.; Yang, Y.;
Lessing, T.; Szabo,
Yu, Y.; Ma, S. Org. Chem. Front. 2016, 3, 1705. (k) Kessler, S. N.;
Backvall, J.-E. Angew. Chem., Int. Ed. 2016, 55, 3734.
5) For reviews on such ring-opening reactions involving cyclo-
propanols, see: (a) Nithiy, N.; Rosa, D.; Orellana, A. Synthesis 2013, 45,
́
K. J. J. Am. Chem. Soc. 2014, 136, 7563. (j) Luo, H.;
̈
(
3199. (b) Rosa, D.; Nikolaev, A.; Nithiy, N.; Orellana, A. Synlett 2015,
26, 441. For seminal papers, see: (c) Park, S.-B.; Cha, J. K. Org. Lett.
2000, 2, 147. (d) Okumoto, H.; Jinnai, T.; Shimizu, H.; Harada, Y.;
Mishima, H.; Suzuki, A. Synlett 2000, 629. (e) Rosa, D.; Orellana, A. Org.
Lett. 2011, 13, 110.
ASSOCIATED CONTENT
Supporting Information
■
(6) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis
*
S
1
991, 234. (b) Lee, J. C.; Sung, M. J.; Cha, J. K. Tetrahedron Lett. 2001,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03637.
4
2, 2059.
(7) For a recent report on the synthesis of allenyl ketones from allenyl
carbonates, see: Zhu, T.; Ma, S. Chem. Commun. 2017, 53, 6037.
Experimental procedure, spectroscopic data (PDF)
H and C NMR spectra of all products (PDF)
(
8) Crystal data for compound 3ea: C H BrO, MW = 417.33,
1
13
25 21
monoclinic, space group P2(1)/c, final R indices [I > 2σ(I)], R =
1
0
1
9
.0295, wR = 0.0738; R indices (all data), R = 0.0436, wR = 0.0811, a =
2
1
2
Accession Codes
6.2736(6) Å, b = 14.3858(5) Å, c = 8.6941(3) Å, α = 90.00°, β =
3
CCDC 1555049 and 1579063 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
4.7750(10)°, γ = 90.00°, V = 2028.30(12) Å , T = 296(2) K, Z = 4,
reflections collected/unique 23191/3559 [Rint = 0.0267], no. of
observations [> 2σ(I)] 2806, parameters: 244.
(9) (a) Theobald, N.; Shoolery, J. N.; Djerassi, C.; Erdman, T. R.;
Scheuer, P. J. J. Am. Chem. Soc. 1978, 100, 5574. (b) Fujimoto, Y.;
Morisaki, M.; Ikekawa, N. J. Chem. Soc., Perkin Trans. 1 1975, 2302.
(
c) Burger, A.; Roussel, J.-P.; Hetru, C.; Hoffmann, J. A.; Luu, B.
Tetrahedron 1989, 45, 155. For a review, see: (d) Hoffmann-Roder, A.;
Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196.
(10) Crystal data for compound (R)-3am: C H ClO, MW = 372.87,
̈
AUTHOR INFORMATION
Corresponding Authors
■
25
21
orthorhombic, space group P2(1)2(1)2(1), final R indices [I > 2σ(I)],
R = 0.0569, wR = 0.1299; R indices (all data), R = 0.1404, wR =
*
E-mail: mqjia@fudan.edu.cn.
E-mail: masm@sioc.ac.cn.
1
2
1
2
*
0
.1736, a = 7.1672(7) Å, b = 8.0143(8) Å, c = 35.791(3) Å, α = 90.00°, β
3
ORCID
= 90.00°, γ = 90.00°, V = 2055.8(3) Å , T = 296(2) K, Z = 4, reflections
collected/unique 24220/3633 [Rint = 0.1128], number of observations
Shengming Ma: 0000-0002-2866-2431
Notes
[
> 2σ(I)] 3633, parameters: 233.
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b03637
Org. Lett. XXXX, XXX, XXX−XXX