Convenient synthesis of adamantyl-substituted β -lactams via uncatalyzed staudinger reaction

Article abstract of DOI:10.1080/00397911.2011.622061

A series of C3-position adamantyl-substituted β-lactams were synthesized via uncatalyzed Staudinger reaction between adamantylketene generated by thermal Wolff rearrangement of the corresponding diazo ketone and various imines. The stereochemical outcome of the reaction was mainly the formation of trans-products, a result attributed to a two-step mechanism leading to the most stable products.

Full text of DOI:10.1080/00397911.2011.622061

This article was downloaded by: [Linkopings universitetsbibliotek]
On: 28 February 2013, At: 12:50
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Convenient Synthesis of Adamantyl-
Substituted β-Lactams via Uncatalyzed
Staudinger Reaction
Mingshun Liu a b , Yaqing Chen a b & Nanyan Fu a b
a Ministry of Education Key Laboratory of Analysis and Detection
Technology for Food Safety, and Department of Chemistry, Fuzhou
University, Fujian, China
b State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, China
Accepted author version posted online: 27 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Mingshun Liu , Yaqing Chen & Nanyan Fu (2013): Convenient Synthesis of
Adamantyl-Substituted β-Lactams via Uncatalyzed Staudinger Reaction, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:7, 1055-1062
To link to this article: http://dx.doi.org/10.1080/00397911.2011.622061
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 1055–1062, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.622061
CONVENIENT SYNTHESIS OF ADAMANTYL-
SUBSTITUTED b-LACTAMS VIA UNCATALYZED
STAUDINGER REACTION
Mingshun Liu,1,2 Yaqing Chen,1,2 and Nanyan Fu1,2
1Ministry of Education Key Laboratory of Analysis and Detection
Technology for Food Safety, and Department of Chemistry, Fuzhou
University, Fujian, China
2State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin, China
GRAPHICAL ABSTRACT
Abstract A series of C3-position adamantyl-substituted b-lactams were synthesized via
uncatalyzed Staudinger reaction between adamantylketene generated by thermal Wolff
rearrangement of the corresponding diazo ketone and various imines. The stereochemical
outcome of the reaction was mainly the formation of trans-products, a result attributed
to a two-step mechanism leading to the most stable products.
Keywords Adamantane; b-lactam; Staudinger reaction; stereoselectivity; thermal Wolff
rearrangement
INTRODUCTION
Adamantane possesses a fascinating ring system and has been frequently used
in organic reactions because of this unique symmetrical cage structure. Furthermore,
its derivatives exhibit significant antiviral, antibacterial, anti-inflammatory, and cen-
tral nervous system biological activities, so a great number of functionalized mole-
cules containing the adamantyl moiety have been designed and synthesized during
recent decades.[1] b-Lactams are an important class of compounds possessing a wide
range of antibiotic activities, and for this reason a large number of methodologies
Received March 31, 2011.
Address correspondence to Nanyan Fu, Ministry of Education Key Laboratory of Analysis and
Detection Technology for Food Safety, and Department of Chemistry, Qi Shan Campus of Fuzhou
University, 2 Xue Yuan Road, University Town, Fuzhou, Fujian 350108, P. R. China. E-mail:
nayan_fu@fzu.edu.cn
1055

1056
M. LIU, Y. CHEN, AND N. FU
have been developed for their synthesis.[2] In terms of efficiency and stereochemical
predictability, the Staudinger reaction is undoubtedly the most widely used route to
b-lactams.[3] Because of the unique structure and potential biological activity of
adamantane, we have investigated the combination of the adamantyl moiety with
the b-lactam skeleton, as few studies of adamantyl-substituted b-lactams have been
reported.[4] Herein, we report a convenient method to synthesize a series of b-lactams
substituted at the C3 position by the adamantyl group via uncatalyzed Staudinger
reaction between 1-adamantylketene, generated by thermal Wolff rearrangement
of the corresponding diazo ketone, with various imines.
Substituted b-lactams are important compounds that attract research interest
for both synthetic and pharmaceutical applications. Their four-membered ring
skeleton is difficult to synthesize because of its ring strain.[5] In 1989, Calet and
coworkers[4a] prepared a series of 1-(1-adamantyl)-b-lactams from ring expansion
of adamantyl-substituted aziridines by rhodium(I)-catalyzed carbonylation. Subse-
quently, Ohno and coworkers[4b] reported the preparation of the versatile synthetic
intermediate 1-adamantyl(ethoxycarbonyl)ketene from the adamantyl-substituted
a-diazo-b-oxo ester by photolysis or solution-spray flash vacuum pyrolysis (600 ꢀC)
or in the presence of rhodium(II) acetate in dichloromethane. The generated ketene
reacted with N-benzylidenenamine to yield the 3-(1-adamantyl)-b-lactam.
In this report we describe a convenient method for the preparation of adamantyl-
substituted b-lactams using the uncatalyzed thermal Wolff rearrangement, including a
study of the stereoselectivity of the reaction.
RESULTS AND DISCUSSION
The uncatalyzed Wolff reaction of 1-diazoacetyladamantane was chosen as the
method for the preparation of adamantyl-substituted b-lactams as this offers the dis-
tinct advantage in the Staudinger reaction of a clean reaction system without the use of
any additives that could affect the cis=trans ratio of the b-lactam products,[6] and also
avoids the possibility of photochemical reaction of the products, which could occur if a
light-induced reaction is used. 1-Adamantyl diazo ketone 4 was prepared as shown in
Scheme 1. Commercially available 1-bromoadamantane (1) was reacted with formic
acid at low temperature in sulfuric acid, forming 1-adamantanecarboxylic acid (2).
1-Adamantanecarbonyl chloride (3), obtained from carboxylic acid 2 under reflux in
thionyl chloride, reacted with diazomethane to yield diazo ketone 4 in 85% yield.
Adamantylketene was generated in situ by thermal Wolff rearrangement of
diazo ketone 4 in xylenes at 140 ꢀC and reacted in situ with substituted imines 5
by [2 þ 2] cycloaddition reaction without catalyst, giving C3-position adamantyl-
substituted diastereoisomeric b-lactams 6 (Scheme 2). The yields and stereochemical
distribution of the reaction products are shown in Table 1.
Scheme 1. Synthetic route for 1-adamantyl diazo ketone 4 from 1-bromoadamantane (1).

ADAMANTYL-SUBSTITUTED b-LACTAMS
1057
Table 1. Stereochemical outcome of [2 þ 2] cycloaddition between 4 and 5
Entry
R1
R2
Product
cis=trans
Yield (%)a
1
2
3
4
5
CH3O
H
H
CH3O
H
6a
6b
6c
6d
6e
0.05:1
0.10:1
0.10:1
0.30:1
0.38:1
67
78
82
7
H
O2N
O2N
CH3O
H
51
aThe isolated yield of trans-6.
The cis- or trans-stereochemistry of the b-lactams was established on the basis
of their 1H NMR spectra. The coupling constant values for the signals corresponding
to the C3 and C4 protons were 6.0–6.4 Hz for the cis-isomers and 2.0–2.8 Hz for the
trans-isomers, in agreement with previously reported values.[7]
As seen in Table 1, the trans-products were isolated as the main products of the
Staudinger reaction between adamantylketene and various imines. These results can
be explained by adamantylketene belonging to the class of ‘‘Moore ketene,’’ which
possesses the moderately electron-donating adamantyl substituent and has a prefer-
ence for trans-b-lactam formation.[8] Moreover, with the increase of the electron-
withdrawing ability of the substituent on the imines, the ratio of cis=trans-products
increased from 0.05:1 to 0.38:1 (entries 1–5). These results indicate that the electron-
withdrawing substituent on imines will increase the formation of cis-products. The
reaction mechanism proposed by Jiao and coworkers can explain our results quite
well.[9] They proposed that electron-donating ketene substituents and electron-
withdrawing imine substituents accelerate the direct ringclosure, leading to an
increased preference for cis-b-lactam formation, whereas electron-withdrawing ketene
substituents and electron-donating imine substituents slow the direct ring closure,
leading to a preference for trans-b-lactam formation (Scheme 3).
b-Lactam 6d prepared from adamantylketene with imine 5d is formed in poor
yield and is difficult to isolate. Surprisingly, amide 11 was obtained as the main pro-
duct in the reaction conditions. The possible mechanism involves attack of the nitro-
gen atom of the imine 5d on the carbonyl carbon of the adamantylketene, forming a
zwitterionic intermediate 7, which undergoes a conrotatory ring closure, leading to
the formation of the b-lactam product 6d. However, the intermediate 7 is highly
moisture sensitive and is attacked at the carbon of the imine moiety of 7 by the water
existing in the reaction system even in very low concentration to form another
zwitterionic intermediate 8. After the proton transfer from intermediate 8 to enolate
Scheme 2. Preparation of diastereoisomeric b-lactams 6 by [2 þ 2] cycloaddition of 4 and 5.

1058
M. LIU, Y. CHEN, AND N. FU
Scheme 3. Proposed mechanism for the formation of cis- and trans-b-lactams.
9 and the tautomerization of enolate 9 to ketone 10, amide 11 is formed by a
rearrangement of the unstable ketone 10 with the breaking of C-N bond under the
reaction conditions (Scheme 4). However, the possibility that imine was unstable
and hydrolyzed to the aniline first, and this reacted with ketene to form amide 11,
cannot be excluded. Similar results have been reported previously.[10,11]
In conclusion, we developed a convenient method to synthesize a series of C3-
position adamantyl-substituted b-lactams via uncatalyzed Staudinger reaction
between adamantylketene generated by the thermal Wolff rearrangement of the
corresponding diazo ketone and various imines. Mainly trans-products are formed,
a result attributed to a two-stage mechanism proceeding through the least crowded
transition state.
Scheme 4. Possible mechanism for the formation of product 11.

ADAMANTYL-SUBSTITUTED b-LACTAMS
1059
EXPERIMENTAL
Melting points were determined with an Electrothermal X-4 series digital
melting-point apparatus and are uncorrected. Infrared (IR) spectra were recorded
on a Perkin-Elmer 2000 series Fourier transform (FT) IR spectrometer. The
NMR spectra were recorded on Bruker Avance 400-MHz spectrometer. The chemi-
cal shifts were quoted in parts per million (ppm) in d values against tetramethylsilane
(TMS) as an internal standard, and the coupling constants were calculated in hertz.
The low-resolution mass spectra (LRMS) and the high-resolution mass spectra
(HRMS) were taken on an Applied Biosystems (Sciex) QStar spectrometer.
Synthesis of 1-Adamantanecarboxylic Acid (2)
A flask charged with 98% concentrated sulfuric acid (125 mL) was stirred in an
ice-water bath. 1-Bromoadamantane (1) (5.4 g, 25 mmol), hexane (15 mL), and formic
acid (15 mL) dropwise were added to it. After 5 h for reaction, the mixture was poured
into the ice water (100 mL) and washed with 5% solution of sodium hydroxide. The
separated aqueous phase was acidified by concentrated hydrochloric acid (pH 2) and
then extracted with chloroform. After removal of solvent under reduced pressure, the
residue was obtained as a white solid (5.2 g, 96%).[12]
Synthesis of 2-Diazo-1-(1-adamantyl)-ethanone (4)
Thionyl chloride (3 ml) and 1-adamantanecarboxylic acid (2) (1.1 g, 6.1 mmol)
were refluxed in benzene (10 ml) at 80 ꢀC for 5 h. Then benzene and excess thionyl
chloride was removed in vacuo. After distilling the residual under reduced pressure,
a colorless 1-adamantanecarbonyl chloride (3) was collected as a liquid. The liquid
turned into a white solid quickly at room temperature.
Carbonyl chloride 3 (1.0 g, 5 mmol) in 5 mL ether was added dropwise to a stir-
red, precooled solution of freshly prepared diazomethane (20 mmol) in 40 mL ether,
and then the mixture was stirred in an ice-water bath overnight. The solvent was eva-
porated under reduced pressure. Purification of the residue by column chromato-
graphy on silica gel (elution with petroleum ether=ethyl acetate ¼ 4:1 v=v) gave the
ꢀ
=
diazo ketone asꢁy1e[l1l3o] w solid (0.67 g, 85%). mp 70–72 C; IR (KBr): 2099 (C N2),
=
1621 (C O) cm
.
General Procedure for the Preparation of b-Lactams 6a–e
A flame-dried, three-neck flask was charged with a solution of imine (0.2 mmol)
in 10 mL of dry xylenes. The flask was immersed in an oil bath and heated to reflux. A
solution of diazo ketone (0.26 mmol) in 5 mL of dry xylenes was then added through a
dropping funnel during a period of 10 min. After the addition, the resulting solution
was stirred for another 12 h at the same temperature. After removal of the solvent, the
residue was purified by flash chromatograghy to remove highly polar impurities. The
product mixture was analyzed by 1H NMR spectrum to determine the cis=trans ratio.
Column chromatograghy of the crude mixture on silica gel afforded the correspond-
ing cis- and trans-b-lactam products.[9]

1060
M. LIU, Y. CHEN, AND N. FU
(ꢂ)-trans-1-Phenyl-4-methoxyphenyl-3-adamantylazetidin-2-one (trans-6a).
1
White solid, yield 67%; mp 155–157 C; IR (KBr): 1727 (C O) cmꢁ1; H NMR
(400 MHz, CDCl3): d 1.64–1.85 (m, 12H, Ad-H), 2.03 (s, 3H, Ad-H), 2.81 (d,
J ¼ 2.0 Hz, 1H, C3-H), 3.81 (s, 3H, OCH3), 4.86 (d, J ¼ 2.4 Hz, 1H, C4-H), 6.90 (d,
J ¼ 8.8 Hz, 2H, Ar-H), 7.03 (t, J ¼ 7.2 Hz, 1H, Ar-H), 7.23–7.32 (m, 6H, Ar-H);
13C NMR (100 MHz, CDCl3): d 28.2, 34.0, 36.8, 40.0 (C-Ad), 55.0 (OCH3), 55.3
ꢀ
=
(C3-H), 71.8 (C4-H), 114.5, 116.9, 123.5, 127.2, 129.0, 130.7, 137.7, 159.4 (C-Ar),
þ
=
166.8 (C O); ESI-MS: m=z 388.2 ([M þ H] ). HRMS (ESI): calcd for C26H30NO2
([M þ H]þ): 388.2277; found: 388.2256.
(ꢂ)-cis-1-Phenyl-4-methoxyphenyl-3-adamantylazetidin-2-one
(cis-6a).
White solid, yield 3%; mp 218–221 C; IR (KBr): 1741 (C O) cmꢁ1; H NMR
(400 MHz, CDCl3): d 1.41–1.62 (m, 12H, Ad-H), 1.78 (s, 3H, Ad-H), 3.32 (d,
J ¼ 6.0 Hz, 1H, C3-H), 3.74 (s, 3H, OCH3), 5.17 (d, J ¼ 6.0 Hz, 1H, C4-H), 6.78 (d,
J ¼ 8.8 Hz, 2H, Ar-H), 7.20–7.34 (m, 7H, Ar-H); ESI-MS: m=z 388.2 ([M þ H]þ).
1
ꢀ
=
(ꢂ)-trans-1-Methoxyphenyl-4-phenyl-3-adamantylazetidin-2-one (trans-
ꢁ1
;
1H
ꢀ
=
6b). White solid, yield 78%; mp 173–175 C; IR (KBr): 1726 (C O) cm
NMR (400 MHz, CDCl3): d 1.68–1.85 (m, 12H, Ad-H), 2.04 (s, 3H, Ad-H), 2.81
(d, J ¼ 2.4 Hz, 1H, C3-H), 3.75 (s, 3H, OCH3), 4.85 (d, J ¼ 2.4 Hz, 1H, C4-H), 6.79
(d, J ¼ 8.8 Hz, 2H, Ar-H), 7.24 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.28–7.39 (m, 5H, Ar-H);
13C NMR (100 MHz, CDCl3): d 28.2, 34.0, 36.8, 40.0 (C-Ad), 55.4 (OCH3), 59.1
(C3-H), 71.8 (C4-H), 114.3, 118.1, 126.0, 128.0, 129.1, 131.3, 138.9, 155.8 (C-Ar),
þ
=
166.1 (C O); ESI-MS: m=z 388.2 ([M þ H] ); HRMS (ESI): calcd for C26H30NO2
([M þ H]þ): 388.2277; found: 388.2260.
(ꢂ)-cis-1-Methoxyphenyl-4-phenyl-3-adamantylazetidin-2-one (cis-6b).
1
White solid, yield 7%; mp 232–233 C; IR (KBr): 1742 (C O) cmꢁ1; H NMR
ꢀ
=
(400 MHz, CDCl3): d 1.41–1.65 (m, 12H, Ad-H), 1.78 (s, 3H, Ad-H), 3.32 (d,
J ¼ 6.0 Hz, 1H, C3-H), 3.75 (s, 3H, OCH3), 5.17 (d, J ¼ 6.0 Hz, 1H, C4-H), 6.78 (d,
J ¼ 9.2 Hz, 2H, Ar-H), 7.21 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.30–7.34 (m, 5H, Ar-H);
ESI-MS: m=z 388.2 ([M þ H]þ).
(ꢂ)-trans-1-Phenyl-4-phenyl-3-adamantylazetidin-2-one (trans-6c). White
ꢁ1
;
1H NMR
ꢀ
=
solid, yield 82%; mp 194–195 C; IR (KBr): 1731 (C O) cm
(400 MHz, CDCl3): d 1.69–1.86 (m, 12H, Ad-H), 2.04 (s, 3H, Ad-H), 2.83 (d,
J ¼ 2.8 Hz, 1H, C3-H), 4.90 (d, J ¼ 2.4 Hz, 1H, C4-H), 7.04 (t, J ¼ 7.2 Hz, 1H,
Ar-H), 7.23–7.39 (m, 9H, Ar-H); 13C NMR (100 MHz, CDCl3): d 28.2, 34.1, 36.8,
40.0 (C-Ad), 55.4 (C3-H), 71.8 (C4-H), 116.9, 123.6, 126.0, 12þ8.1, 129.0, 129.1,
=
137.6, 138.8 (C-Ar), 166.6 (C O); ESI-MS: m=z 358.2 ([M þ H] ). HRMS (ESI):
calcd for C25H28NO ([M þ H]þ): 358.2171; found: 358.2154.
(ꢂ)-cis-1-Phenyl-4-phenyl-3-adamantylazetidin-2-one (cis-6c). White solid,
yield 8%; mp 214–216 C; IR (KBr): 1741 (C O) cmꢁ1; 1H NMR (400 MHz, CDCl3):
ꢀ
=
d 1.41–1.65 (m, 12H, Ad-H), 1.79 (s, 3H, Ad-H), 3.34 (d, J ¼ 6.4 Hz, 1H, C3-H), 5.22
(d, J ¼ 6.0 Hz, 1H, C4-H), 7.03 (m, 1H, Ar-H), 7.22–7.36 (m, 9H, Ar-H); ESI-MS: m=z
358.2 ([M þ H]þ).
(ꢂ)-trans-1-Nitrophenyl-4-methoxyphenyl-3-adamantylazetidin-2-one
(trans-6d). White solid, yield 7%; mp 148–151 C; IR (KBr): 1726 (C O) cmꢁ1; 1H
ꢀ
=

ADAMANTYL-SUBSTITUTED b-LACTAMS
1061
NMR (400 MHz, CDCl3): d 1.66–1.83 (m, 12H, Ad-H), 2.04 (s, 3H, Ad-H), 2.78 (d,
J ¼ 2.4 Hz, 1H, C3-H), 3.74 (s, 3H, OCH3), 4.93 (d, J ¼ 2.0 Hz, 1H, C4-H), 6.79 (d,
J ¼ 9.2 Hz, 2H, Ar-H), 7.17 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.50 (d, J ¼ 8.8 Hz, 2H,
Ar-H), 8.22 (d, J ¼ 8.8 Hz, 2H, Ar-H); ESI-MS: m=z 433.2 ([M þ H]þ); HRMS
(ESI): calcd for C26H29N2O4([M þ H]þ): 433.2127, found: 433.2139.
(ꢂ)-cis-1-Nitrophenyl-4-methoxyphenyl-3-adamantylazetidin-2-one (cis-
1
6d). White solid, yield 3%; mp 217–220 C; IR (KBr): 1744 (C O) cmꢁ1; H NMR
ꢀ
=
(400 MHz, CDCl3): d 1.41–1.63 (m, 12H, Ad-H), 1.81 (s, 3H, Ad-H), 3.44 (d,
J ¼ 6.4 Hz, 1H, C3-H), 3.75 (s, 3H, OCH3), 5.24 (d, J ¼ 6.0 Hz, 1H, C4-H), 6.80 (d,
J ¼ 8.8 Hz, 2H, Ar-H), 7.14 (d, J ¼ 9.2 Hz, 2H, Ar-H), 7.56 (d, J ¼ 8.4 Hz, 2H,
Ar-H), 8.21 (d, J ¼ 7.2 Hz, 2H, Ar-H); ESI-MS: m=z 433.2 ([M þ H]þ).
(ꢂ)-trans-1-Phenyl-4-nitrophenyl-3-adamantylazetidin-2-one (trans-6e).
1
White solid, yield 51%; mp 254–256 C; IR (KBr): 1737 (C O) cmꢁ1; H NMR
ꢀ
=
(400 MHz, CDCl3): d 1.67–1.84 (m, 12H, Ad-H), 2.04 (s, 3H, Ad-H), 2.80 (d,
J ¼ 2.0 Hz, 1H, C3-H), 4.98 (d, J ¼ 2.0 Hz, 1H, C4-H), 7.05 (t, J ¼ 6.8 Hz, 1H,
Ar-H), 7.22–7.28 (m, 4H, Ar-H), 7.51 (d, J ¼ 8.4 Hz, 2H, Ar-H), 8.22 (d, J ¼ 8.4 Hz,
Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d 28.1, 34.3, 36.7, 40.1 (C-Ad), 54.6
(C3-H), 72.2 (C4-H), 116.7, 124.1, 124.5, 126.9, 129.3, 137.1, 146.5, 147.8 (C-Ar),
þ
=
165.6 (C O); ESI-MS: m=z 403.2 ([M þ H] ). HRMS (ESI): calcd. for C25H27N2O3
([M þ H]þ): 403.2022; found: 403.2029.
(ꢂ)-cis-1-Phenyl-4-nitrophenyl-3-adamantylazetidin-2-one (cis-6e). White
1
solid, yield 18%; mp 189–191 C; IR (KBr): 1748 (C O) cmꢁ1; H NMR (400 MHz,
ꢀ
=
CDCl3): d 1.41–1.64 (m, 12H, Ad-H), 1.82 (s, 3H, Ad-H), 3.46 (d, J ¼ 6.4 Hz, 1H,
C3-H), 5.29 (d, J ¼ 6.4 Hz, 1H, C4-H), 7.07 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.19 (d,
J ¼ 7.6 Hz, 2H, Ar-H), 7.24–7.28 (m, 2H, Ar-H), 7.58 (s, br, 2H, Ar-H), 8.21 (s, br,
2H, Ar-H); ESI-MS: m=z 403.2 ([M þ H]þ).
N-(4-Methoxyphenyl)-1-adamantylacetamide (11)
1
White solid, yield 64%; mp 164–165 C; IR (KBr): 1652 (O C-NH) cmꢁ1; H
ꢀ
=
NMR (400 MHz, CDCl3): d 1.63–1.73 (m, 12H, Ad-H), 1.99 (s, 3H, Ad-H), 2.07 (s,
=
2H, CH2C O), 3.79 (s, 3H, OCH3), 6.85 (d, J ¼ 8.8 Hz, 2H, Ar-H), 6.99 (s, 1H,
N-H), 7.41 (d, J ¼ 8.8 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d 28.6, 33.3,
36.7, 42.7 (C-Ad), 52.7 (CH2), 55.5 (OCH3), 114.1, 121.8, 131.0, 156.4 (C-Ar),
=
þ
169.2 (C O); ESI-MS: m=z 300.1 ([M þ H] ).
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (No. 20702005), the Scientific Research Foundation of State Key Laboratory
of Elemento-organic Chemistry of Nankai University (No. 0811), the Scientific
Research Foundation for the Returned Overseas Chinese Scholars, State Education
Ministry (No. LXKQ0802), and Fujian Provincial Natural Science Foundation of
China (No. 2008J0148). We thank Xiao-Qing Zhu from Nankai University and

1062
M. LIU, Y. CHEN, AND N. FU
Annette D. Allen from the University of Toronto for spectroscopic measurements
and discussion.
REFERENCES
1. Fort, R.C. Jr. Adamantane: The Chemistry of Diamond Molecule; Marcel Dekker:
New York, 1976.
2. (a) For reviews, see Fu, N.; Tidwell, T. T. Preparation of b-lactams by [2 þ 2] cycloaddi-
tion of ketenes and imines. Tetrahedron 2008, 64, 10465–10496; (b) Palomo, C.; Aizpurua,
J. M.; Ganboa, I.; Oiarbide, M. Asymmetric synthesis of b-lactams by Staudinger
ketene-imine cycloaddition reaction. Eur. J. Org. Chem. 1999, 3223–3235.
´
3. (a) Cossıo, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. A semiempirical theor-
etical study on the formation of b-lactams from ketenes and imines. J. Am. Chem. Soc.
1993, 115, 995–1004. (b) Arriete, A.; Lecea, B.; Cossı
outcome in the Staudinger reaction between acyl chlorides and imines. J. Org. Chem.
1998, 63, 5869–5876; (c) Cossıo, F. P.; Arrieta, A.; Sierra, M. A. The mechanism of the
´
o, F. P. Origins of the stereodivergent
´
ketene-imine (Staudinger) reaction in its centennial: still an unsolved problem? Acc. Chem.
Res. 2008, 41, 925–936.
4. (a) Calet, S.; Urso, F.; Alper, H. Enantiospecific and stereospecific rhodium(I)-catalyzed
carbonylation and ring expansion of aziridines: Asymmetric synthesis of b-lactams and
the kinetic resolution of aziridines. J. Am. Chem. Soc. 1989, 111, 931–934 (b) Ohno,
M.; Itoh, M.; Ohashi, T.; Eguchi, S. Ethyl 3-(1-adamantyl)-2-diazo-3-oxopropanoate:
Synthetic use for the preparation of some adamantane derivatives. Synthesis 1993,
793–796.
5. Cromwell, N. H.; Phillips, B. The azetidines: Recent synthetic developments. Chem. Rev.
1979, 79, 331–358.
6. Xu, J. Stereoselectivity in the synthesis of 2-azetidinones from ketenes and imines via the
Staudinger reaction. Arkivoc 2009, 9, 21–44.
7. Banik, B. K.; Becker, F. F. Unprecedented stereoselectivity in the Staudinger reaction
with polycyclic aromatic imines. Tetrehedron Lett. 2000, 41, 6551–6554.
8. Georg, G. I.; He, P.; Kant, J.; Wu, Z. J. Stereocontrolled synthesis of N-vinyl-, N-(10-
propenyl)-, and N-unsubstituted-b-lactams from 2-aza-1,3-butadienes via the Staudinger
reaction. J. Org. Chem. 1993, 58, 5771–5778.
9. Jiao, L.; Liang, Y.; Xu, J. Origin of the relative stereoselectivity of the b-lactam formation
in the Staudinger reaction. J. Am. Chem. Soc. 2006, 128, 6060–6069.
10. Jiao, L.; Liang, Y.; Wu, C.; Huang, X.; Xu, J. Reaction of imidates with phenoxyacetyl
chloride. Chem. Res. Chin. U. 2005, 21, 59–64.
11. Allen, A. D.; Godoy, J.; Fu, N.; Nagy, M.; Spadaro, S.; Tidwell, T. T.; Vukovic, S. Spiro-
aziridine and bislactam formation from bisketene–imine cycloadditions. J. Am. Chem.
Soc. 2008, 130, 2386–2387.
12. Cai, X.-H.; Hu, W.; Yao, Z.-F.; Liu, Z.-H. Preparation of rimantadine hydrochloride.
Chin. J. Med. Chem. 2002, 12, 161–163.
13. Brockmann, R.; Schneider, K.; Mass, G. Wolff rearrangement of (1-diazo-2- oxoalkyl)
silanes. Tetrahedron 1989, 45, 5517–5530.